The present disclosure is directed to methods and materials for the treatment and/or prevention of gout in a subject. Such methods and materials may be used to treat a mammalian (e.g., human) subject suffering from gout or to prevent occurrence of the same in an at risk subject.
Gout is a form of acute arthritis that causes severe pain and swelling in the joints. Gouty arthritis accounted for an estimated 3.9 million outpatient visits in the United States in 2002. Unlike other rheumatic diseases, the etiology of gout is well characterized, its pathophysiology is well understood, and the disease is easily diagnosed. For many patients, therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids for acute attacks and prevention of recurrence with agents that lower the serum uric acid levels are highly effective. However, these therapies are not sufficient for many patients with acute, chronic or refractory gout due to their lack of adequate clinical efficacy, associated toxicities, or because of co-morbid diseases.
Gout is precipitation of crystals into tissue, usually in and around joints, most often causing recurrent acute or chronic arthritis.
The disease is marked by deposits of monosodium urate (MSU) crystals into tissue, usually in and around the joints and in the synovial fluid and lining, and usually an excessive amount of uric acid in the blood. Intense joint inflammation occurs as white blood cells engulf the uric acid crystals, causing pain, heat, and redness of the joint tissues. Gouty arthritis is due to monosodium urate crystal-induced release of proinflammatory cytokines from leukocytes. Among the many cytokines implicated, IL-1 may have a special role in the inflammatory network, as MSU crystals stimulate IL-1 release by monocytes and synovial mononuclear cells. Acute gout flares usually come on suddenly, go away after 5 to 10 days, and can keep recurring.
IL-1β is a pro-inflammatory cytokine secreted by a number of different cell types including monocytes and macrophages. When released as part of an inflammatory reaction, IL-1β produces a range of biological effects, mainly mediated through induction of other inflammatory mediators such as corticotrophin, platelet factor-4, prostaglandin E2 (PGE2), IL-6, and IL-8. IL-1β induces both local and systemic inflammatory effects through the activation of the IL-1 receptor found on almost all cell types. The interleukin-1 (IL-1) family of cytokines has been implicated in a number of disease states. IL-1 family members include IL-1α, IL-1β, and IL-1Ra. Although related by their ability to bind to IL-1 receptors (IL-1R1 and IL-1R2), each of these cytokines is different, being expressed by a different gene and having a different primary amino acid sequence. Furthermore, the physiological activities of these cytokines can be distinguished from each other.
Experiments indicating the apparent involvement of IL-1β and other inflammatory mediators in gout have been published (see for example, Petrilli et al., Joint Bone Spine (2007) 74:571-576; Pope et al., Arthritis Rheum. (2007) 56:3183-3188; Chen et al., J. Clin. Invest. (2006) 116:2073-2075; Akahoshi, T., et al., Curr. Opin. Rheumatol. (2007) 19:146-150; Martinon, F., et al., Nature (2006) 440:237-241; and Cronstein et al., Arthritis Res. Ther. (2006) 8, Suppl. 1:S3). So et al., Arthritis Res. Ther. (2007) 9(2):R28 describe the use of a recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) in an open label study for the treatment of acute gout, performed with daily dosing of 100 mg subcutaneously for 3 days. McGonagle, et al., Ann. Rheum. Dis. (2007) 66:1683-1684 describe the use of a recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) for the treatment of gout in a patient receiving continuous daily subcutaneous doses of 100 mg. The daily dosing of injectable medications is generally undesirable and may result in problems with patient compliance, thereby decreasing effectiveness of this treatment modality/or limiting its desirability. Thus, there remains a need for effective means to treat gout, particularly treatment compositions and methods that do not require frequent (e.g., daily) injections.
Because of the problems with current treatments, new therapies to treat gout are needed to replace or complement available pharmaceutical approaches. The present disclosure provides compositions and methods for the treatment of gout (e.g., acute gout, chronic gout, refractory gout). The methods disclosed herein comprise, for example, administering an anti-IL-1β antibody or fragment thereof. Methods that directly target the IL-1β ligand with an antibody, particularly antibodies that exhibit high affinity, provide advantages over other potential methods of treatment, such as IL-1β receptor antagonists (e.g., IL-1Ra, Anakinra). The challenge for IL-1 receptor antagonist-based therapeutics is the need for such therapeutics to occupy a large number of receptors, which is a formidable task since these receptors are widely expressed on all cells except red blood cells (Dinarello, Curr. Opin. Pharmacol. 4:378-385, 2004). In most immune-mediated diseases, such as the diseases disclosed herein, the amount of IL-1β cytokine that is measurable in body fluids or associated with activated cells is relatively low. Thus, a method of treatment and/or prevention that directly targets the IL-1β ligand should provide a superior strategy, particularly when administering an IL-1β antibody with high affinity.